Dr. Whang, an Instructor in Surgery at Harvard Medical School, aspires to become an independent investigator, working at the interfaces between clinical and basic sciences as he seeks new therapies for gastrointestinal disorders. The long-term goal of this proposal is to develop new strategies for treating patients suffering from the short bowel syndrome. Chronic total parenteral nutrition and intestinal transplantation are currently the only available options for these patients; new approaches are desperately needed. The hypotheses underlying these studies are 1) specific cell cycle regulatory mechanisms mediate intestinal regeneration that occurs during adaptation following massive small bowel resection and 2) an understanding of these mechanisms can be exploited to rationally design methods to maximally augment the regenerative response. Three specific aims will address these hypotheses. The first two aims are to characterize the cell cycle regulatory mechanisms in intestinal regeneration using 1) a reductionist in vitro model and 2) a wild-type and genetically-altered mice lacking specific cell cycle regulators. The third aim is to design and deploy a therapeutic "cocktail" that maximally stimulates intestinal regeneration. During he five-year period of this award, Dr. Whang will acquire expertise with the concepts and methods of studying cell cycle regulation in the gastrointestinal tract. Collaborative mentorship from both a surgical investigation and a basic scientific will allow this young surgeon to obtain the skills necessary to become an independent investigator.